3-substituted derivatives of yohimbane alkaloids and process for their production



United States Patent 3-SUBSTITUTED DERIVATIVES OF YOHIMBANE ALKALOIDS AND PROCESS FOR THEIR PRO- DUCTION John Shavel, Jr., Mendham, and Harold Zinnes, Rockaway, N.J., assignors to Warner-Lambert Pharmaceutical Company, Morris Plains, N.J., a corporation of Delaware No Drawing. Filed July 23, 1963, Ser. No. 296,938

4 Claims. (Cl. 260-288) The present invention relates to new and novel 3-substituted derivatives of yohimbane alkaloids :having the formula:

wherein R represents lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like, aryl such as phenyl or aralkyl such as benzyl; R represents hydrogen, lower al-kyl such as methyl, ethyl, propyl, isopropyl and the like, lower alkoxy such as methoxy or ethoxy or acetyl; R represents hydrogen or lower alkyl and R represents hydrogen, hydroxy or 'keto and .to the nontoxic pharmaceutically acceptable acid addition and quaternary ammonium salts thereof.

This invention also encompasses within its scope processes for the production of these 3-substituted derivatives of yohirnb-ane.

The compounds of this invention have significant and interesting pharmacological activity as analgesics, tranquilizers and anti-inflammatory agents. In addition, these compounds are valuable intermediates in the production of other compounds of the yohimbane series.

The compounds of this invention bear the A, B, C, D and E rings as depicted in the above structural formula and are, generally, alkaloids of the yohimbane series.

The use of a straight line in the above structural formula throughout this specification and in the claims generally denotes the attachment of a radical or s-ubstit-uent at a particular position and is not used to indicate alpha or beta orientation.

It has been found that compounds of this invention may be prepared by treating a 3-dehydroyothimbane salt with an organoli-thium compound of the formula R Li in which R may be lower alkyl, 'aryl or aralkyl as defined above. Other 3-dehydroyohimbane derivatives such as 3-dehydiro-17-hydroxyyohimbane perchlorate, 3-dehydro-l6a-methyl-l7fiahydroxyyohirnbane chloride and the like may also be conveniently employed. The reaction may be represented by the following equation:

3291,80 Patented Dec. 13, 1956 In the above equation, X represents an anion, such as sulfate, chloride, phosphate, perchlorate, acetate and the like. Instead of employing a 3-dehydroyohimb-ane salt as the starting material, 3-cyanoyohimbane of the fori. may also be treated with the lithium compound R Li to give the desired 3-alkyl, aryl or aralkyl substituted yohimbanes. T h e 3-cyianoyonimbane used as the starting material is described and claimed in our copending application entitled 3-Cyano-Yohimbane Derivatives, Serial No. 293,904, filed July 9, 1963, now abandoned.

An alternate pathway for the production of 3-aralkyl substituted yohimbanes is available by treating either a 3- dehydroyohimbane salt or 3-cyanoyohi-mbane with a Grignard reagent of the formula RM-gBr, such as, for example, benzylmagnesium bromide.

Generally, the 3-substit-uted yohimbanes obtained in accordance with the above-described reaction may be modified further to give other derivatives.

Thus, for example, 3-alkyl or 3-aryl substituted l7- hydroxyyohimbanes may be acetylated at lO-position, for example, by reacting with acetylating agents such as acetic anhydride in boron trifluoride. In addition, they may be oxidized to give the corresponding yohimbones and the latter may also be acetylated to give IO-acetylated 3-alkyl or 3-aryl yohimbones. The 10-acetylated 3-substituted yohimbanes may, in turn, be treated to give corresponding IO-hydroxy derivatives. The 10-hydroxy compounds, of course, can be treated with a diazo-lower alkane at room temperature to give l0-lower alkoxy substituted compounds. The process to prep-are these 10- lower alkoxy substituted yohimbanes is described in John Shavels copending application Serial No. 119,829 entitled IO-Substituted Derivatives of Yohimbane Alkaloids and Process Therefor, filed June 27, 1961, now having ma tured to U.S. 3,139,434. These compounds are also within the scope of this invention.

The compounds of this invention may be converted into their pharmaceutically accept-able nontoxic acid addition or quaternary ammonium salts. Useful acid addition salts are those formed with such acids as maleic, fumaric, benzoic, succinic, methylsulfonic, sulfonic, citric, tartaric, salicylic, malic, cinnamic, hydrochloric, hydrobromic, phosphoric and the like. The acid addition salts may be prepared in the conventional manner, for example, by treating a solution or suspension of the free base in an organic solvent with the desired acid, and then recovering the salt which forms by crystallization techniques. The quaternary salts are prepared by heating a solution of the base in a suitable solvent with a reactive alkyl halide such as methyl iodide, ethyl bromide, n-hexyl bromide, benzyl chloride or another reactive ester such as methyl sulfate, ethyl sulfate or methyl p-toluene sulfonate.

For therapeutic use, the new and novel compounds of this invention, either as the free base or in the form of a pharmaceutically acceptable, nontoxic acid addition or quaternary ammonium salt, may be formulated with a conventional pharmaceutical carrier to form tablets, capsules, elixers, solutions, suspensions, suppositories and the like.

The following examples are included in order further to llustrate the present invention. Room temperature as sed hereinafter refers to a temperature range of 20 to C.

EXAMPLE 1 3-methylyohimbane from 3-dehydroyoliimbane perchlorate A mixture of 11.4 g. 3-dehydroyohimbane perchlorate nd 0.25 mol methyllithium in 250 ml. ether is refluxed vith stirring for seven hours. A mixture formed is poured n ice water, the layers are separated, and the aqueous ayer is extracted with ether. The ether solution is disilled to dryness to give an oil which on trituration with 0 ml. methanol yields 2.4 g. of 3-methylyohimbane as he crystalline methanolate, M.P. 127-130 C. (softens t 90 0.), [a1 92 (pyridine, c.=0.65), which gives single spot on ionophoresis and paper chromatography .nd whose ultraviolet spectrum (in acidified ethanol) hows complete absence of 3-dehydroyohimbane. Re- =rystallization from methanol gives a purified material dried in vacuo at 80 C.), M.P. 130-132 C. (softens .t 90 C.), [@1 91 (pyridine, c.=0.62), [121 64 chloroform, c.=0.55), [M 62 (ethanol, c.=0.60).

Analysis for C H N CH OH: Calc.: C, 77.25; H,

.26; N, 8.58. Found: C, 77.04; H, 9.15; N, 8.32.

' A sample is dried in vacuo at 110 C. for 8 hours to give material, M.P. 130l32 C., [ab 98 (pyridine, r.=0.65), [0:] 70 (chloroform, c.=0.62), [21 67 ethanol, c.=0.59)

3 1 24203270, 752, 74s, vggg 3470, 1294. were 225 36,600), 272 (shoulder: 7250 279-282 7500 289 6400 m 245 2200 286 (6300) Analysis for C H N Calc.: C, 81.58;. H, 8.90; N, L52. Found: c, 81.83; H, 9.04; N, 9.73.

EXAMPLE 2 3-methylyohimbane from 3-cyanoyohimbane To a solution of 0.5 mol methyllithium in 375 ml. ether added a solution of 15.3 g. 3-cyanoyohimbane in 200 nl. dry benzene. An additional 550 ml. more benzene s added and the mixture is refluxed with stirring for :ight hours, the reflux temperature being 56 C. It is )OUI'Cd on ice water, the layers are separated, and the tqueous layer is extracted with three 200 ml. portions of :ther. The combined organic layer is washed with 30 n1. water and then extracted with five 250 ml. portions )f aqueous acetic acid. The acetic acid solution is Jasified with ammonium hydroxide and the resulting prezipitate is collected by filtration, washed with water, dried, 'ecrystallized from 50 ml. methanol, and dried in vacuo at 80 C. to give 6.6 g. of 3-methylyohimbane, M.P. l27130 C. (softens at 90 C.), [12], 91 (pyridine, :.=0.54), which gives a single spot on ionophoresis and aaper chromatography corresponding exactlywith those given by 3-methylyohimbane prepared in accordance with Example 1. The ultraviolet spectrum in acidified ethanol solution shows complete absence of the max. at 350 mu which is characteristic of 3-dehydroyohimbane salts.

EXAMPLE 3 S-phenylyokimbane from 3-dehydr0y0himbane perchlorate A mixture of 11.4 g. B-dehydroyohimbane perchlorate and 0.3 mol phenyllithium in 400 ml. ether is refluxed with stirring for nineteen hours. The reaction mixture is poured on ice water, the layers separated and the aqueous layer then extracted with ether. The combined ether solution is dried over sodium sulfate and is treated with ethereal hydrogen bromide. The first material to precipitate is collected and recrystallized from acetone to give 1.7 g. of yellow crystals which could. be shown by ionophoresis and ultraviolet spectrum to be 3-dehydr0- yohimbane chloride. On the addition of more ethereal hydrogen bromide there is obtained a dark green gum which solidifies on trituration with water. The solid is recrystallized once from acetonitrile and once from methanol to give 1.3 g. 3-phenylyohimbane hydrobromide, M.P. 287 -294 C. dec. (starts to darken at ca. 220 C.).

Analysis for C H N Br- /2CH OH: Calc.: C, 67.54; H, 6.89; N, 6.18; Br, 17.63. Found: C, 67.84; H, 6.79; N, 5.89; Br, 17.68.

A suspension of 700 mg. of the recrystallized hydrobromide in an excess of aqueous ammonium hydroxide is shaken with methylene chloride. The methylene chloride solution is dried over sodium sulfate and distilled to dryness to give a residue which is recrystallized from methanol to give 400 mg. of 3-phenylyohimbane base, M.P. 237240 C. dec., [a] =179 (pyridine, 07 0.62). The acetonitrile and methanol filtrates from the hydrobromide recrystallization are evaporated to dryness and the residue is dissolved in 100 ml, methanol, and an excess of aqueous ammonium hydroxide is added. A small amount of dark insolubles is filtered off, the solution is heated to boiling, and ml. water is added. The yel low precipitate which separates on cooling to room temperature is collected by filtration, washed with water, dried, and is recrystallized from methanol to give 1.5 g. of 3-phenylyohirnbane base, M.P. 235239 C. dec., [a] '=177 (pyridine, c.=0.57). Recrystallization from methanol gives material, M.P. 238-241 C. dec. (starts to darken at 197 C.), [0t]1 =181 (pyridine, c.=0.54), [a] =l60 (chloroform, c.=0.5l).

Analysis for C H N Calc.: C, 84.22; H, 7.92; N, 7.86. Found: C, 84.43;H, 8.12; N, 8.03.

EXAMPLE 4 3-phenylyohim' 'bane from 3-cynn0y0himbane To 0.5 mol phenyllithium in 400 ml. ether is added a solution of 15.3 g. 3-cy-anoyohimbane in 800 ml. benzene, and the mixture is refluxed with stirring for ten hours. It is poured on ice water, the layers are separated, and the aqueous layer is extracted withether. The combined organic layer is extracted with five 200 ml. portions of 20% aqueous acetic acid, washed with two portions of aqueous ammonium hydroxide, dried over sodium sulfate, and distilled to dryness. The residue is triturated with 30 ml. methanol to give 4.7 g. of 3-phenylyohimbane as crystals, M.P. 235-238 C. dec., [a] =l76 (pyri dine, c.=0.65), which gives a single spot on ionophoresis and paper chromatography and whose ultraviolet spectrum shows it to be free of 3-dehydroyohimbane.

EXAMPLE 5 3-benzyly0himbane Benzylmagnesium bromide is prepared by dropwise addition of a solution of 34 g. benzyl bromide in 400 ml. ether to a stirred suspension of 15.8 g. magnesium in ml. ether. When addition is completed the mixture is stir-red at room temperature for one hour longer and then refluxed forty-five minutes. To the Grignard reagent thus prepared is added 12 g. 3-dehydroyohimbane chloride. The reaction mixture is stirred at room temperature ,for 4 hours, allowed to stand at room temperature overnight, and is then poured into a solution of 30 g. ammonium chloride in 600 ml. ice water. After separation of the layers, the aqueous layer is extracted with several portions of ether, the combined ether solution is dried over sodium sulfate, and is evaporated to dryness. The residue is dissolved in 200 ml. 50% acetic acid, water is added to reduce the acetic acid concentration to 15%, and partial neutralization to pH 4 is carried out by the addition of ammonium hydroxide. The aqueous solution is decanted from the gum which precipitates and the latter is dissolved in methylene chloride. This solution is dried over sodium sulfate, evaporated to dryness, and the residue is crystallized from methanol to give 6.7 g. of 3-benzylyohimbane, M.P. 221 -222 C. dec., [a] 193 (chloroform, c.=0.55). In addition there is obtained 0.8 g. of a second crop, M.P. 214216 dec., [a] =-199 (chloroform, c.=0.54). Recrystallization of the first crop from methanol gives material, M.P. 222223 C., [u] =-192 (chloroform, c.=0.56), [a] =--4 (pyridine, c.==0.51), pm 3420, 1600, 760, 740, 730 emr X331? 225 (39,000), 275 (shouder: 7500), 282-283 (8000), 240 (7000), min 253 (3500), 288 (6800) my.

Analysis for C H N Calc.: C, 84.28; H, 8.16; N, 7.56. Found: C, 84.05; H, 8.29; N, 7.76. I

EXAMPLE 6 3,16a-dimethyl-17a-hydroeryyohimbane A mixture of 16.5 g. 3-dehydro-16a-methyl-17a-hydroxyyohimbane chloride, 0.5 mol methyllithium, 400 ml. ether, and 900 ml. benzene is refluxed with stirring for seven hours.v It is poured on ice Water, the layers are separated, and the aqueous layer is extracted with ether. The combined organic layer is washed with water, extracted with five 200 ml. portions of 15% acetic acid, and the acetic acid solution is basified with ammonium hydroxide. The resulting precipitate is filtered off, washed with water, dried, and recrystallized twice from ethyl acetate to give 5.5 g. of 3,16a-dimethyl-17u-hydroxyyohimbane, M.P. 206-213 C. dec. (darkens at 195 C.), [a] =+l4 (pyridine, c.=0.61). Another recrystallization from the same solvent gives material, M.P. 211- 222 C. dec., [a] =+l4 (pyridine, c.=0.61).

Analysis for C H N O: Calc.: C, 77.74; H, 8.70; N, 8.64. Found: C, 77.95; H, 8.56; N, 8.84.

EXAMPLE 7 3,16a-dimethylyohim bone A mixture of 8.8 g. of 3,16a-dimethyl-17a-hydroxyyohimbane, 550 ml. xylene, and 220 ml. cyclohexanone is distilled at atmospheric pressure until 100 ml. of distillate is collected. After cooling to room temperature, 39 g. of aluminum phenoxide is added and refluxed with stirring for 24 hours. The reaction mixture is cooled to room tempearture and is extracted with three 275 ml. portions of 40% potassium hydroxide. The organic layer is extracted with five 250 ml. portions 15 acetic acid, the aqueous solution is made strongly basic with ammonium hydroxide and extracted with chloroform. The dried chloroform solution is distilled in vacuo to give an oil which solidifies on trituration with petroleum ether. This solid is collected and recrystallized from ethanol to give 5.0 g. (two crops) of 3,16cx-dimethylyohimbone, M.P. 255-260 C. dec., [a] =-69 (pyridine, c.=0.83). Recrystallization from methanol gives material, M.P. 255 260 C. dec., [a] :70 (pyridine, c.=0.60).

Analysis for C H N O: Calc.: C, 78.22; H, 8.13; N, 8.69. Found: C, 78,45; H, 8.22; N, 8.76.

EXAMPLE 8 3-methyl-1 7fl-hydr0xyyohim bane A mixture of 33 g. S-dehydro-17B-hydroxyyohimbane chloride, 1 mol methyllithium, 875 ml. ether, and 2000 ml. dry benzene is refluxed with stirring for twenty hours. It is poured on ice Water, the layers are separated, and the aqueous layer is extracted with ether. An insoluble solid which remains at the interface is collected by filtration. It weighs 4.1 g. and is shown by ionophoresis and paper chromatography to consist completely of S-dehydro- 17 8-hydroxyyohimbane base. The combined organic layers are dried over sodium sulfate and distilled at atmospheric pressure until the resulting mixture begins to bump. It is filtered while hot to give 3.7 g. of crystalline material which is also shown to consist wholly of 3-dehydro-17fi hydroxyyohimbane base. The filtrate is extracted with 15 acetic acid, and the aqueous solution is made basic with ammonium hydroxide. The resulting precipitate is filtered off, Washed with water, and sucked dry. Ionophoresis and paper chromatography shows it to be almost free of the starting B-dehydro compound. It is dried by azeotropically distilling with benzene and is triturated with 25 ml. methanol to give 11.4 g. of 3-methyll7fi-hydroxyyohimbane, M.P. 136138 C. (with evolution of gas) [a] =75 (pyridine, c.=0.62). Recrystallization from methanol gives material (dried in vacuo at C. for 16 hours), M.P. 139142 C. (With evolution of gas), [0c] =73 (pyridine, c.=0.60).

Analysis for C H N O- /2CH OH: Calc.: C, 75.51; H, 8.64. Found: C, 75.58; H, 8.60.

A sample is dried in vacuo at 140 C. for 3 hours, M.P. l44148 C., [a] =8O (pyridine c.=0.73).

Analysis for C H N O: Calc.: C, 77.38; H, 8.44; N, 9.02. Found: C, 77.10; H, 8.66; N, 8.99.

The two crops of 3-dehydro-17,6-hydroxyyohimbane base are combined and recrystallized from methanol to give 5.4 g. of material [a] =-|69 (pyridine, c.=0.60).

EXAMPLE 9 3-methylyohimb0ne A mixture of 6.2 g. 3-methyl-17,8-hydroxyyohimbane, 300 ml. dry benzene, and ml. cyclohexanone (previously dried over sodium sulfate) is distilled at atmospheric pressure until 300 ml. distillate is collected. The mixture is cooled to room tempearture, 26 g. aluminum phenoxide is added, and it is refluxed for 53 hours after which 'a paper chromatogram shows that only about 75% conversion has taken place. The reaction mixture is extracted with three 200 ml. portions of 40% potassuim hydroxide followed by four 100 ml. portions of 15% acetic acid. The acetic acid solution is basified with ammonium hydroxide and the resulting solid is collected by filtration. It is dissolved in chloroform, the solution is dried over sodium sulfate and is concentrated to a volume of about 150 ml. This is chromatographed over a Florisil volumn (55 g.) using chloroform as the eluant. The first 300 ml. of eluate is evaporated to dryness to yield 2.3 g. of 3-methylyohimbone, M.P. 152157 C., [a] =86 (pyridine, c.=0.53 whose chromatogram showed it to be completely free of the starting alcohol. Recrystallization from acetonitrile gives material, M.P. l72 C [a] =88 (pyridine, c.=0.74).

Analysis for C H N O: Calc.: C, 77.88; H, 7.84; N, 9.08. Found: C, 77.80; H, 7.92; N, 9.20.

Further elution of the column with chloroform followed by chloroform containing l% and 5% methanol, respectively, gives 1.75 g. of the starting alcohol as is shown by its paper chromatogram.

EXAMPLE l0 10-acetyl-3-methylyohimb0ne A solution of 20 ml. acetic acid in 200 ml. acetic anhydride is saturated with boron trifluoride by passing in the latter for about 15 minutes, maintaining a temperature of 15 to 25 C. To this is slowly added a solution of 6 g. 3-methylyohimbone in 30 ml. acetic acid. The reaction mixture is stirred at 15 to 25 C. for three hours, poured on ice water, made strongly basic with ammonium hydroxide, and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate and distilled in vacuo to dryness. A solution of the residue and 3.5 g. sodium methoxide in 150 ml. methanol is refluxed for 30 minutes. The methanol is removed by distillation in vacuo, 100 ml. water is added, and the resulting solid is filtered off, washed with water, and sucked dry. It is further dried by dissolving in benzene and distilling to dryness. The residue is redissolved in 50 ml. chloroform and is chromatographed over 60 g. Florisil, using chloroform as the eluant. The first 1000 ml. of eluate is evaporated to dryness and the :sidue is recrystallized from benzene to give 1.3 g. of -acetyl-3-methylyohimbone, M.P. 263265 C. dec., u] =-56 (pyridine, c.=0.54).

13 2 3360, 1710, 1670, 1624, 1595, 808 em.- XfifZg 257 41,700), 290-300 (9000), A 226 (6000), 278(7500), m Analysis for C H N O Calc.: C, 75.40; H, 7.48; I, 7.99. Found: C, 75.62; H, 7.32; N, 8.26.

EXAMPLE 1 1 3-methyl-1 7-hydr0xy-18-benzylideneyohimbane A mixture of 29 g. 3-dehydro-17-hydroxy-18-henzylleneyohimbane chloride, 0.7 mol methyllithium in 560 11. ether, and 1400 ml. benzene is refluxed with stirring or twenty-seven hours. The reaction mixture is poured n ice water, the layers are separated and the aqueous iyer is extracted with several portions of ether. The ombined organic layers are extracted with four 400 ml. ortions of acetic acid and the aqueous solution is made strongly basic with ammonium hydroxide. The iixture is extracted with chloroform and the dried chlooform solution is evaporated to dryness to give an amorhous material whose ultraviolet spectrum shows it to e a mixture of the desired 3-methyl compound and the tarting 3-dehydro compound. The material is redisolved in 375 ml. acetic acid, filtered and 375 ml. water is added. The solid which separates out is filtered ff, washed with 100 ml. 15% acetic acid followed by .00 ml. water, and then slurried with dilute ammonium tydroxide solution; it is collected, washed with water, and ucked dry. The ultraviolet spectrum shows that only trace of the starting 3-dehydro compound is present. the solid is recrystallized to yield 2.2 g. of a first crop rf 3-methyl-17-hydroxy-l8-benzylideneyohimbane in the orm of White crystals and two further crops are obtained )1: concentration of the filtrate. The second and third :rops are recrystallized again from methanol to yield :rystals which are combined with those of the first crop 0 give a total of 3.5 g. of material, M.P. 262-264 C. tec., [ot] =340 (pyridine, c.=0.68). Recrystallizaion of a portion from methanol gives material, M.P. L62263 C. dec., [a] =335 (pyridine, c.=0.66).

Analysis for C H N O: Calc.: C, 81.16; H, 7.82; N, 7.01. Found: C, 81.08; H, 7.84; N, 7.12.

It is to be understood that the foregoing detailed de- ;cription is given merely by 'way of illustration and that nany variations may be made therein without departing from the spirit of our invention.

Having described our invention, what We desire to secure :3 Letters Patent is:

1. S-phenylyohimbane melting with decomposition at Z35238 C. and having an optical rotation of about [ed -176 (pyridine, c.=0.65).

2. Process for the production of a compound of the formula:

wherein R is a member selected from the group consisting of lower alkyl, phenyl and benzyl and R is a member selected from the group consisting of hydrogen and lower alkyl and R is a member selected from the group consisting of hydrogen and 'hydroxy which comprises refiuxing amember selected from the group consisting of those having the formula:

4 in which X is an anion selected from the group consisting of acetate, chloride, sulfate, phosphate and perchlorate and R and R have the same meaning as defined with a compound of the formula R' Li.

3. Process for the production of a compound of the formula wherein R' is benzyl and R is a member selected from the group consisting of hydrogen and lower alkyl and R is a member selected from the group consisting of hydrogen and hydroxy which comprises refluxing a member selected from the group consisting of those having the formula: 1

9 in which X is an anion selected from the group consisting of sulfate, chloride, perchlorate, phosphate and acetate witha compound of the formula R'MgBr in which R' has the same meaning as defined.

4. 3-benzylyohimbane melting at 214216 C. with decomposition and having an optical rotation of about [ab -192 (chloroform, c.=0.56) and [a] 4 (pyridine, c.=0.51).

10 References Cited by the Examiner UNITED STATES PATENTS 3,048,593 8/ 1962 Shavel et a1 2 60288 3,096,245 7/1963 Shavel et a1 16767 15 3,120,528 2/1964 Shavel 260287 3,139,428 6/ 1964 Shavel et al 260240 FOREIGN PATENTS 2/ 1961 France.

OTHER REFERENCES Corsano et 2112 Chem. Abs., vol. 53 (1959), p. 20107.

Karrer: Helv. Chim. Act-a, vol. 35 (1952), pp. 1932 and 1933.

Muller et al.: Naturwissenschaften, vol. 47 (1960), p. 82.

Swan: J. Chem. Soc. (1950), p. 1534.

Vejdelek et a1.: Chem. Abs., vol. 53 (1959), p. 3256.

Wenkert et aL: Jonr. Amer. Chem. Soc., vol. 81 (1959), p. 1476.

WALTER A. MO'DANCE, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

J. A. PATTEN, Assistant'Examiner. 

2. PROCESS FOR THE PRODUCTION OF A COMPOUND OF THE FORMULA: 